Disability and Therapeutic Response in Paediatric Neuromyelitis Optica Spectrum Disorder: A Case Series from Iran.

Objectives: The characteristics of paediatric neuromyelitis optica spectrum disorder (NMOSD) may indicate the degree of disability and identify factors that predict the response to treatment. Materials & Methods Among 114 NMOSD patients in an acquired demyelinating syndromes registry at the Sina Hospital, in Tehran, Iran, 10 paediatric NMOSD patients with longitudinal follow-up from 2005 to 2016 were retrospectively identified. The median time between disease onset and diagnosis was 18 months (range 1-108 months). Results All patients had a relapsing course, which resulted in disability in six with severe visual impairment and functional blindness in one and impaired ambulation in five patients during follow-up. Azathioprine (AZA) was first drug of choice for prophylaxis, but in five patients new attacks occurred and therapy was switched to rituximab (RTX) with no further relapses after median two years (range 1-3 y) follow-up. Conclusion: Paediatric onset of NMOSD was associated with severe attacks and poor response in 50 % of cases to AZA, RTX seemed to decrease the relapse rate.


Introduction
Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune inflammatory disease of the central nervous system (1). In most cases, an autoantibody to the astrocytic water channel protein aquaporin-4 (AQP4-IgG) can be detected (2). AQP4-IgG causes complement-dependent astrocyte injury, inflammation, and consequent demyelination besides axonal damage (2,3). A high relapse rate and disability accumulation in NMOSD can cause severe neurological disabilities, which can potentially be prevented or modified by appropriate treatment (3).
An early onset of NMOSD is defined as disease onset prior to 18 years (y) of age (4). The paediatric onset of NMOSD comprises 4% of all cases (4).
Paediatric NMOSD rarely occurs before the age of nine, with a variable median age (5,6). The Paediatric Working Group for Neuromyelitis optica spectrum disorder (NMOSD) has stated that adult consensus criteria are applicable to paediatric patients (1). However, some differences have been noted such as a lower female-male ratio (3:1) compared with adults (9:1), more cases with a monophasic course, and less specificity of a longitudinally extensive transverse myelitis (LETM) lesion on spinal cord MRI (7).
We aimed to review and analyse detailed data of paediatric onset of NMOSD cases including clinical manifestations and treatment responses, the data underscore the presence of severe disability in paediatric patients and may assist in the identification of factors that predict the response to treatment.

Of the 114 NMOSD patients registered in the Sina
Hospital NMOSD Clinic of the Tehran University of Medical Sciences, Tehran, Iran, 10 showed paediatric onset ( 18 y of age). These cases were diagnosed from 2005 to 2016. Their clinical symptoms, laboratory data and MRI findings were reviewed and questionnaires were used to provide long-term retrospective data. All patients had been diagnosed according to last international consensus criteria of NMOSD (1).

Ethics approval
Oral and written informed consent was obtained from all participants. The study was carried out in accordance with the Tehran University of Medical Sciences Ethical Committee guidelines.

Statistical analysis
Statistical differences were tested using the Wilcoxon rank sum test for two-group comparisons and the Fisher exact test for group comparisons of categorical variables. A P-value < 0.05 was considered significant.

Demographic data and clinical course
The demographic and clinical characteristics of the patients are depicted in Table 1 AQP4-IgG positive) aged under 18 yr at disease onset were included. The female-male ratio was 4:1. The median age at disease onset was 13 y (range: 8-17 y). The median age of the patients at the disease diagnosis was 14 yr (range: 10-26 yr).
Thirty-four relapses were recorded for all patients.

Clinical presentation
The initial presentation in four of the patients was  every six months over the next two years. The median annual relapse rate changed from 1 (range 0.6-2) before preventive therapy to 0.5 (range 0-2) after the therapy with azathioprine ( Table 2).
Five of the patients had their treatment switched to rituximab (RTX) because of new relapse on treatment with azathioprine, while no further relapse occurred with RTX in these five patients within two years (Table 2). RTX was administered as 1 g given IV 2 weeks apart and then repeated every 6 months. No severe complications occurred with RTX. The median expanded disability status scale (EDSS) before preventive therapy was 3 (0-5 range) and decreased to 2.5 (range 0-5) after preventive therapy (Table 3). RTX is an anti-CD20 chimeric monoclonal antibody that depletes B cells and is used in autoimmune and inflammatory CNS disorders including NMOSD (10). In adult NMOSD one prospective and 3 retrospective, RTX reduced the annualized relapse rate (10). One prospective paediatric study of RTX reported that RTX was effective in relapse prevention (11). In the present study after starting preventive treatment, the median annual relapse rate decreased. Although the lowering of EDSS was not significant after preventive treatment probably because of the small sample size, the median relapse rate decreased significantly. The current case series is the first Iranian report on RTX treatment of paediatric NMOSD.
In Conclusion, paediatric onset of NMOSD does occur. As a consequence, NMOSD may be considered a differential diagnosis for paediatric MS. The clinical phenotype was compatible with other reports of paediatric NMOSD cases.
Disability occurred incrementally as a result of attacks. It seems that the immunosuppressive treatment for paediatric NMOSD patients may decrease the relapse rate and that RTX is a superior treatment option. Larger studies are required to further evaluate long-term disability in this regard.